The primary goal of this project is to test the hypothesis that two bone-related genes - osteonectin, which is a secreted extracellular matrix protein over-expressed in a wide range of advanced human cancers, and osteoactivin, which is a structurally unrelated transmembrane protein also over-expressed in several cancers - play important roles in the pathological process of glioma invasion. Although many of the genetic alterations that dysregulate the cell processes of growth and death involved in tumor initiation have been elucidated in recent years, less progress has been made in the complex but critical processes of tumor invasion, metastasis, and angiogenesis. Invasion is particularly important in the pathophysiology of gliomas as tumor cell infiltration of normal brain prevents curative resection. With this emphasis, our preliminary results suggest that osteonectin and osteoactivin can mediate critical tumor cell behaviors. We have shown that the expression of osteonectin and osteoactivin can induce spontaneous metastases and tumor cell invasion into the brain along penetrating blood vessels. Hypothesis: We hypothesize that osteonectin and osteoactivin expression can induce glioma invasion through the modification of tumor microenvironment, and that these mechanisms can be targeted to inhibit glioma invasion. To firmly establish the role of osteonectin and osteoactivin in the pathophysiology of gliomas and elucidate the mechanism by which osteonectin and osteoactivin functions to lay the foundation for the development of novel therapeutics directed towards osteonectin and osteoactivin, we will focus our studies on the following two Specific Aims: 1) Define the contributions of osteonectin and osteoactivin to the invasive phenotype of glioma. 2) Validate osteonectin and osteoactivin as potential therapeutic targets in glioma invasion. It is hoped that these studies will provide the basis of novel therapeutic interventions for patients with malignant gliomas.